Project Summary Mesolimbic dopamine (DA) projections from the ventral tegmental area (VTA) to nucleus accumbens (NAc) serve a fundamental role in goal-seeking. This neural circuit is thus central to adaptive behavior (e.g., finding food), but can also promote psychopathologies characterized by hyper-motivation (e.g., drug abuse or obesity) or hypo- motivation (e.g., apathy or depression), all of which exact an enormous toll on individual an economic health. Afferent projections from numerous brain regions synapse onto VTA DA neurons to control their activity. The current proposal aims to identify how specific inputs to DA neurons contribute to their role in motivated behaviors and disease states. This work will focus on two primary mechanisms controlling brain DA function and reward- related behavior. First, the lateral hypothalamus (LH) has been the subject of intense research for well over 50 years due to its fundamental role in virtually all aspects of motivated behaviors, reward processing, and reward consumption. Second, the endocannabinoid (eCB) system is a vast signaling network that acts throughout the brain and periphery to regulate numerous homoeostatic processes, but serves a particularly important role in modulating brain DA function. We will use state-of-the art techniques to identify cell type- and neural circuit- specific mechanisms by which eCB signaling controls LH influence on DA neurons and how these mechanisms contribute to specific components of food-seeking behaviors. We will then assess similarities and differences between the neuronal mechanisms that control food seeking versus drug-seeking by investigating their role in the voluntary intake of amphetamine, one of the most widely abused drugs worldwide. Together, these experiments aim to elucidate the functional overlap and distinctions between precise neural circuit mechanisms that control adaptive versus aberrant forms of reward-driven behavior, with the ultimate goal of fundamentally understanding motivated actions and developing safe and effective treatments for aberrant forms of reward seeking that characterize, for example, drug abuse or obesity.